Definition of fatty acid transport protein-2 (FATP2) structure facilitates identification of small molecule inhibitors for the treatment of diabetic complications

• Published in: International journal of biological macromolecules Vol. 244; p. 125328
• Main Authors: Kumar, Mukesh, Gaivin, Robert J., Khan, Shenaz, Fedorov, Yuriy, Adams, Drew J., Zhao, Weiyang, Lee, Hsueh-Yun, Dai, Xinghong, Dealwis, Chris G., Schelling, Jeffrey R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 31.07.2023
• Subjects: Biological Transport; Diabetes Complications; Diabetes Mellitus; Drug Discovery; FATP2; Fatty Acid Transport Proteins; Fatty Acids; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; FATP2; Molecular dynamics simulation; Drug discovery
• ISSN: 0141-8130; 1879-0003; 1879-0003
• DOI: 10.1016/j.ijbiomac.2023.125328

Diabetes is a major public health problem due to morbidity and mortality associated with end organ complications. Uptake of fatty acids by Fatty Acid Transport Protein-2 (FATP2) contributes to hyperglycemia, diabetic kidney and liver disease pathogenesis. Because FATP2 structure is unknown, a homology model was constructed, validated by AlphaFold2 prediction and site-directed mutagenesis, and then used to conduct a virtual drug discovery screen. In silico similarity searches to two low-micromolar IC50 FATP2 inhibitors, followed by docking and pharmacokinetics predictions, narrowed a diverse 800,000 compound library to 23 hits. These candidates were further evaluated for inhibition of FATP2-dependent fatty acid uptake and apoptosis in cells. Two compounds demonstrated nanomolar IC50, and were further characterized by molecular dynamic simulations. The results highlight the feasibility of combining a homology model with in silico and in vitro screening, to economically identify high affinity inhibitors of FATP2, as potential treatment for diabetes and its complications.